The present invention relates to a theophylline sustained release tablet and, more specifically it relates to a multi unit type sustained release tablet.
Theophylline is a useful medicine frequently used as an agent for treating symptoms of bronchial asthma. It is known in the art that its range of effective blood level is about 10 to 20 xcexcg/ml. However, if the concentration of theophylline in the blood exceeds 20 xcexcg/ml, it is pointed out that serious side effects sometimes appear with regard to the cardiovascular system and the central nervous system. Further, there is a large difference in blood levels among individuals. Various conditions (e.g., cardiac insufficiency, liver and kidney disease, etc.), age differences, smoking, etc. also have large effects. Further, theophylline has a short biological half-life of about 6 hours for adults. In order to maintain the effective blood level, four times doses per day have been considered necessary. However, such frequent dosage is troublesome to patients, reduces patient compliance, and causes the state of the disease to become worse. In particular, attacks of bronchial asthma often occur at daybreak. It is not possible to sufficiently prevent such attacks with just ingestion before going to bed, and therefore, repeat ingestion close to daybreak is necessary. Thus, in the past, continuous effort has been made to develop a sustained release type theophylline formulation. Several formulations are already available on the market.
Among the theophylline sustained release formulations known up to now, there have been those of the type dispersing the medicament in a matrix composed of an insoluble synthetic resin or lipid (for example, Japanese Unexamined Patent Publication (Kokai) No., 56-122311, U.S. Pat. No. 4,590,062, etc.), those having a structure where beads having various types of different release rates are contained in capsules or tablets and these beads are formed with alternative layers of active ingredients and layers of insoluble lipid around a core (for example, U.S. Pat. No. 3,860,733), etc. Among these theophylline sustained release formulations, there are those which are already marketed, but each has defects which cannot be ignored in actual use. None of these types can be said to be perfected yet as sustained release formulations.
That is, the former types of formulations had the defect that, since the ratio of the vehicle and excipient for the dispersion of the medicament reached as high as 50% or more, a reduction in the content of the medicament and an increase in the size of the tablet could not be avoided and, further, the medicament was not released perfectly. Further, the latter types of formulations had the defect that they required a high degree of skill, since the complicated operations are necessary for the formulation thereof, and therefore, the manufacturing costs also became high.
The present inventors previously proposed sustained release formulations for theophylline in Japanese Examined Patent Publication (Kokoku) No. 57-53325, Japanese Unexamined Patent Publication (Kokai) No. 3-193733, and Japanese Examined Patent Publication (Kokoku) No. 07-29927.
Accordingly, the present invention is to provide a formulation of a multi unit type for which those dose a day is sufficient and for which formulation is easy.
The present inventors engaged in intensive study to achieve the above-mentioned object of the present invention and, as a result, found that it is possible to make the size of the tablet smaller than the conventional theophylline formulations and further to obtain a tablet having a superior sustained release effect whereby the present invention is completed.
Thus, in accordance with the present invention, there is provided a theophylline sustained release tablet characterized in the core granules composed mainly of theophylline are made into coated granules coated with at least one coating film layer composed of a hydrophobic material and a plastic excipient and, optionally, containing an enteric polymer material and the coated granules are then compressed together with a disintegrating excipient.